Oncolytics Biotech and Roche are launching a new study for multi-indication gastrointestinal (GI) cancer in Germany. The phase 1/2 trial, known as GOBLET, will investigate the use of pelareorep, in combination with Roche's anti-PD-L1 checkpoint inhibitor atezolizumab (Tecentriq), in patients with metastatic colorectal and advanced or metastatic pancreatic and anal cancers.

Pelareorep is an intravenous therapy that uses an isolate of a double-stranded RNA virus called reovirus that is found in stagnant water and sewage. This virus can penetrate noncancer cells but is unable to replicate in normal cells. In cancer cells, the compound induces selective tumor lysis and promotes an inflamed tumor phenotype by inducing innate and adaptive immune responses.

“An important attribute of pelareorep is that it can be given intravenously,” Thomas C. Heineman, MD, PhD, global head of clinical development and operations at Oncolytics Biotech, told 

. “Most oncolytic viruses are given intratumorally. The ability to give pelareorep intravenously has the obvious benefit of convenience, but it also allows the virus to target metastatic sites that may not be accessible by intratumoral injection. Also, should future studies indicate the need, intravenous administration makes it much easier to provide booster courses of therapy compared with intratumoral administration."

Enrollment in the GOBLET trial (which is not yet listed on ClinicalTrials.gov) is planned to begin in the first half of 2021, Heineman said.

The study will be conducted at multiple centers in Germany and will be managed by AIO, an academic cooperative medical oncology group based in Germany. “If this study shows promising results, then I anticipate that we would move into controlled studies to confirm any clinical benefit, and I expect those would be multinational studies that include the United States. I would anticipate that those studies would be multinational studies that would include North America and the United States,” Heineman said.

The primary end point of the study is safety, with overall response rate and blood-based biomarkers (T cell clonality and CEACAM6) as exploratory endpoints. About 55 patients are planned for enrollment across 4 separate cohorts.

Two cohorts will be with patients with colorectal cancer. In 1 cohort, 14 patients with third-line metastatic colorectal cancer will receive pelareorep in combination with atezolizumab and TAS-102 (trifluridine/tipiracil; Lonsurf). Another cohort will recruit 19 patients with first-line microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer to receive pelareorep in combination with atezolizumab.

A third cohort will recruit 12 patients with metastatic pancreatic cancer for first-line treatment with pelareorep in combination with atezolizumab, gemcitabine (Gemzar), and nab-paclitaxel (Abraxane). A fourth cohort will enroll 10 patients with advanced and unresectable anal cancer for second-line treatment with pelareorep in combination with atezolizumab.

“This is a small study designed to identify a signal, so the cohort sizes range from 10 to 19 patients to allow statistical comparison to historical data,” Heineman said. “In any of the cohorts, if prespecified criteria are met for tumor response and there are no safety issues or concerns, we’ll expand to larger cohorts to better define the efficacy signal.”

The GOBLET study builds on an earlier trial showing that pelareorep-based combination treatments stimulated an adaptive immune response in patients with KRAS mutated colorectal cancer.

In that study, pelareorep was combined with bevacizumab (Avastin) and the chemotherapy regimen of FOLFIRI, which consists of folinic acid, fluorouracil, and irinotecan. The study enrolled 36 patients with KRAS mutation in a dose-escalation trial. The combination was well-tolerated, with promising signals of efficacy. Among 30 evaluable patients, 6 (20%) had a partial response (PR) and 22 patients (73.3%) had stable disease (SD) as their best response, for a clinical benefit rate (PR +SD) of 93.3%. Adverse events included myelosuppression, fatigue, and diarrhea.

Another previous study identified CEACAM6 as a prospective biomarker for pelareorep in the treatment of patients with pancreatic cancer.

Heineman said the GOBLET and future studies will continue to look for biomarkers that identify populations of patients in any or all of these cohorts that may benefit from treatment with pelareorep plus checkpoint inhibitors.

Oncolytics Biotech collaborates with Roche and AIO to initiate a phase 1/2 gastrointestinal cancer trial combining pelareorep with Roche’s anti-PD-L1 checkpoint inhibitor. News release. Oncolytics Biotech. October 27, 2020. Accessed December 2, 2020. 

Oncolytics Biotech announces publication of pelareorep’s clinical benefit against KRAS mutated colorectal cancer. News release. Oncolytics Biotech. April 2, 2020. Accessed December 2, 2020. 

Goel S, Ocean AJ, Parakrama RY, Ghalib MH, et al. Elucidation of pelareorep pharmacodynamics in a phase 1 trial in patients with 

-mutated colorectal cancer. Molecular Cancer Therapeutics; 19(5). May 2020. doi:10.1158/1535-7163.MCT-19-1117

Noonan AM, Hays JL, Yount J, Bekaii-Saab TS, et al. CEACAM6 is a candidate biomarker for pelareorep resistance in pancreatic endocarcinoma (PDAC). Presented at: 2020 Gastrointestinal Cancers Symposium sponsored by ASCO, January 23-25. 

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December 30, 2020 - The phase 1/2 GOBLET trial will investigate the use of pelareorep in combination with atezolizumab in patients with metastatic colorectal and advanced or metastatic pancreatic and anal cancers.

Oncolytics Biotech Launches Trial of Pelareorep/Atezolizumab Combo in Difficult-to-Treat GI Cancers

Jounce Therapeutics will evaluate its lead agent vopratelimab in combination with the anti–PD-1 monoclonal antibody JTX-4014, in patients with non-small cell lung cancer (NSCLC) who have not received immunotherapy.

The clinical-stage immunotherapy company is still working to recover from a recent setback with vopratelimab in this disease. The company announced on November 3, 2020, that enrollment to the EMERGE trial exploring vopratelimab plus ipilimumab (Yervoy) (NCT03989362) would be halted.

Vopratelimab, is a monoclonal antibody that binds to and activates ICOS, a protein on the surface of certain T cells that may stimulate an immune response against tumor cells.

Investigators reviewing preliminary results from the phase 2 trial determined the combination was unlikely to succeed. Only 1 patient displayed an objective response and only 9 of 50 patients in the trial remain on treatment.

“We are disappointed that an early look at the EMERGE data indicates that we will not meet our pre-specified interim criteria for continued enrollment,” Jounce chief medical officer Beth Trehu, MD, said in a statement.

The company is proceeding with the phase 2 SELECT trial (NCT04549025), which began enrollment in October. The trial (N = 75) compares the safety and efficacy of vopratelimab plus JTX-4014 versus JTX-4014 alone in patients with NSCLC who are positive for the TISvopra predictive biomarker. Eligible patients may have not received therapy with a PD-1/PD-L1 inhibitor and have progressed on a platinum-based chemotherapy regimen.

The primary endpoint is mean percent change from baseline in all measurable lesions. Secondary endpoints include progression-free survival (PFS), objective response, median duration of response, and median overall survival (OS).

Investigators expect to have preliminary efficacy data from SELECT in 2021.

TISvopra is an 18-gene RNA tumor inflammation signature optimized to predict the emergence of ICOS-high CD4 T cells. Investigators will screen patients in SELECT for the TISvopra biomarker. Jounce estimates that approximately 20% of patients in the trial will be months above the TISvopra threshold and potentially eligible for the trial.

Patients were classified based on tumor inflammation score (TIS) and investigators established a TIS threshold that optimized the predictive emergence of ICOS-high CD4 cells in the presence of vopratelimab. They then applied this threshold to clinical data assessing clinical benefit. 

Jounce is moving ahead with SELECT based in part on results from the phase 1/2 ICONIC trial (NCT02904226).

Among patients who were positive for TISvopra (n = 22) in ICONIC, the median PFS was 2.2 months (95% CI, 2.0-4.6) compared with 1.9 months (95% CI, 1.8-2.0) for those who were negative for TISvopra (n = 67). PFS rate strongly favored the TISvopra-positive group at 6 months (20.1% vs 3.7%) and 9 months (20.1% vs 0%).

The median OS among the TISvopra-positive cohort was 16.9 months versus 6.2 months among the negative cohort (

In a retrospective subset analysis, investigators found that positive for TISvopra score improved RECIST response and was predictive for emergence of an ICOS high CD4 T cell population in patients treated with vopratelimab. In contrast, PD-L1 stats was not predictive for clinical benefit.

Jounce Therapeutics Announces Update on Vopratelimab Program. News release. Accessed December 3, 2020. bit.ly/3ol7Pjw

Yap TA, Gainor JF, Burris HA et. al. Association of a predictive RNA signature (RS) with emergence of ICOS hi CD4 T cells and efficacy outcomes for the ICOS agonist vopratelimab (vopra) and nivolumab (nivo) in patients (pts) on the ICONIC trial. 

December 17, 2020 - Jounce Therapeutics will evaluate its lead agent vopratelimab in combination with the anti–PD-1 monoclonal antibody JTX-4014, in patients with non-small cell lung cancer who have not received immunotherapy.

Vopratelimab/JTX-4014 to be Evaluated in Phase 2 Study for Immunotherapy-Naïve NSCLC 

The novel immunotherapeutic vaccine DSP-7888 (ombipepimut-S or adegramotide/nelatimotide), in combination with pembrolizumab (Keytruda), has been dosed in the first patient with platinum-resistant ovarian cancer, according to Sumitomo Dainippon Pharma Oncology, Inc., the developer of the agent.

DSP-7888 is being evaluated in a phase 1b/2 open-label (NCT03311334), multicenter study; the patient was dosed in the phase 2 expansion portion.

“Patients with platinum-resistant ovarian cancer have a high unmet need with limited treatment options; therefore, we are excited to advance the study of DSP-7888 plus pembrolizumab and evaluate its role and potential benefits,” said Patricia S. Andrews, chief executive officer and global head of oncology at Sumitomo Dainippon Pharma Oncology. “Furthermore, we look forward to better understanding how these combined mechanisms may be able to sensitize this patient population to immunomodulators and improve clinical benefits.”

The anti-cancer vaccine targets the Wilms Tumor 1 (WT1) protein, which is overexpressed in many ovarian cancers. DSP-7888 contains 2 peptides that induce WT1-specific cytotoxic T lymphocytes and helper T cells to attack WT1-expressive cancer cells.

In the phase 1b portion of the trial, patients with solid tumors were evaluated for safety and tolerability with DSP-7888 and a PD-1 checkpoint inhibitor (nivolumab [Opdivo] or pembrolizumab).2 Patients with neoplasms, melanoma, non–small cell lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, urothelial neoplasm, hepatocellular carcinoma, microsatellite instability–high or mismatch repair deficient tumors, colorectal cancer, gastroesophageal junction adenocarcinoma, gastric cancer, cervical cancer, primary peritoneal cancer, platinum-resistant ovarian cancer, serous epithelial ovarian cancer, and fallopian tube cancer were included in the phase 1b portion of the study.

Based on findings from the phase 1b portion, as well as the prevalence of WT1 in patients with ovarian cancer, the phase 2 portion of the study was initiated.

The phase 2 portion will evaluate the preliminary antitumor activity of a dosing emulsion administration of the vaccine plus pembrolizumab with regard to overall response rate (ORR). Patients may be treated for up to 24 months.

Secondary end points include duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), 6-month PFS, overall survival up to 48 months, immune ORR, immune DCR, immune PFS, immune DOR, and safety.

The dosing emulsion administration will be given intradermally DSP-7888 every 7 days until cycle 2 and every 21 days in combination with pembrolizumab.

In addition to having platinum-resistant ovarian cancer, patients have to be positive for at least 1 of these human leukocyte antigens (HLA): HLA-A*02:01, HLA-A*02:06, HLA-A*24:02, HLA-A*03:01, or HLA-B*15:01. Patients also have to be considered platinum resistant to last administered platinum-based therapy, defined as relapse within 6 months after last dose of platinum-based therapy, and have completed at least 1 but no more than 4 prior lines of therapy for serous epithelial ovarian, fallopian tube, or primary peritoneal cancer. Additional inclusion criteria are defined in the study.

Key exclusion criteria include patients with primary platinum-refractory disease, patients with known, untreated brain metastases, patients who received prior treatment with other PD-1/PD-L1 inhibitors or immuno-regulatory receptor inhibitors, such as anti–CTLA-4, LAG-3, IL-2R, or GITR antibodies, patients who have received certain treatments for ovarian cancer within prespecified time frames, patients who have received a live vaccine within 4 weeks prior to first dose of DSP-7888, and patients with any known additional, progressive malignancy that required active treatment, with certain exceptions. Additional exclusion criteria are defined in the study.

The trial is currently recruiting, and the estimated enrollment is 104 patients.

Sumitomo Dainippon Pharma Oncology announces first patient dosed in phase 2 dose-expansion portion of study evaluating investigational WT1 immunotherapeutic cancer vaccine DSP-7888 (ombipepimut-S*) in patients with ovarian cancer. News release. October 27, 2020. Accessed November 25, 2020. 

A study of DSP-7888 dosing emulsion in combination with immune checkpoint inhibitors in adult patients with advanced solid tumors. ClinicalTrials.gov. November 2, 2020. Accessed November 25, 2020. 

December 2, 2020 - The novel immunotherapeutic vaccine DSP-7888, in combination with pembrolizumab, has been dosed in the first patient with platinum-resistant ovarian cancer.

Pipeline Report: November 2020

Articles

Oncolytics Biotech Launches Trial of Pelareorep/Atezolizumab Combo in Difficult-to-Treat GI Cancers

Vopratelimab/JTX-4014 to be Evaluated in Phase 2 Study for Immunotherapy-Naïve NSCLC